Biology subjects

Johnson, M. R.

Publications and source records attributed to Johnson, M. R..

24 records · Page 2Linked to original sources

bioRxiv2020

Signatures Of TSPAN8 Variants Associated With Human Metabolic Regulation And Diseases

Here, with the example of common copy number variation (CNV) in the TSPAN8 gene, we present an important piece of work in the field of CNV detection, CNV association with complex human traits such as 1H NMR metabolomic phenotypes and an example of functional characterization of CNVs among human induced pluripotent stem cells (HipSci). We report TSPAN8 exon 11 as a new locus associated with metabolomic regulation and show that its biology is associated with several metabolic diseases such as type 2 diabetes (T2D), obesity and cancer. Our results further demonstrate the power of multivariate association models over univariate methods and define new metabolomic signatures for several new genomic loci, which can act as a catalyst for new diagnostics and therapeutic approaches.

genomics↗

bioRxiv2020

Diversity of sea star-associated densoviruses and transcribed endogenized viral elements of densovirus origin

A viral etiology of Sea Star Wasting Syndrome (SSWS) has been largely explored using metagenomics leading to the conclusion that a densovirus is the predominant DNA virus associated with this syndrome, and, thus, the most promising viral candidate pathogen. Single-stranded DNA viruses are however highly diverse and pervasive among eukaryotic organisms which we hypothesize may confound the association between densoviruses and SSWS in sea stars. To test this hypothesis and assess the association of densoviruses to SSWS, we compiled past metagenomic data with new metagenomic-derived viral genomes from sea stars collected from Antarctica, California, Washington, and Alaska. We used 179 publicly available sea star transcriptomes to complement our approaches for densovirus discovery. Lastly, we focus the study to SSaDV, the first sea star densovirus discovered, by documenting its biogeography and putative tissue tropism. Transcriptomes contained mostly endogenized densovirus elements similar to the NS1 gene, while >30 complete and near-complete densoviral genomes were recovered from viral metagenomes. SSaDV was associated with nearly all tested species from southern California to Alaska, and in contrast to previous work, we show SSaDV is one genotype among a high diversity of densoviruses present in sea stars across the west coast of the United States and globally that are commonly associated with grossly normal (i.e. healthy or asymptomatic) animals. The diversity and ubiquity of these viruses in wild sea stars confounds the original hypothesis that one densovirus was the etiologic agent of SSWD. ImportanceThe primary interest in sea star densoviruses, specifically SSaDV, has been their association with Sea Star Wasting Syndrome (SSWS), a disease that has decimated sea star populations across the west coast of the United States since 2013. The association of SSaDV to SSWS was originally drawn from metagenomic analyses concluding that it was (1) the only densovirus present in the metagenomic data and (2) the most likely viral candidate based on representation in symptomatic sea stars. We reassessed the original metagenomic data with additional genomic datasets and found that SSaDV was one of ten densoviruses present in the original dataset and was no more represented in symptomatic sea stars than in asymptomatic sea stars. Instead, SSaDV appears to be a widespread, generalist virus that exists among a large diversity of densoviruses present in sea star populations.

genomics↗

bioRxiv2020

Reward impacts visual statistical learning

Humans automatically detect and remember regularities in the visual environment--a type of learning termed visual statistical learning (VSL). Many aspects of learning from reward resemble statistical learning in respects, yet whether and how reward learning impacts VSL is largely unexamined. In two studies, we found that reward contingencies affect VSL, with high-value associated with stronger behavioral and neural signatures of such learning than low-value images. In Experiment 1, participants learned values (high or low) of images through a trial-and-error risky choice task. Unbeknownst to them, images were paired as four types--High-High, High-Low, Low-High, and Low-Low. In subsequent recognition and reward memory tests, participants chose the more familiar of two pairs (a target and a foil) and recalled the value of images. We found better recognition when the first images of pairs have high-values, with High-High pairs showing the highest recognition rate. In Experiment 2, we provided evidence that brain responses were affected by both value and statistical contingencies. When we compared responses between the high-value first image and the low-value first image, greater activation in regions that included inferior frontal gyrus, anterior cingulate gyrus, hippocampus, among other regions were found. These findings were driven by the interaction between statistically structured information and reward--the same value contrast yielded no regions for second-image contrasts and for singletons. Our results suggested that the powerful allocation of attention in response to the high-value first image potentially enables better memory for statistically learned pairs and reward information than low-value first image.

neuroscience↗

bioRxiv2019

A highly prevalent and pervasive densovirus discovered among sea stars from the North American Atlantic Coast

Viral metagenomes prepared from tissues from Forbes sea star (Asterias forbesi) led to the discovery of a complete genome of a novel sea star densovirus (AfaDV). The genome organization of AfaDV and phylogenetic analysis place this virus among the Ambidensovirus genus in the subfamily Densoviridae, family Parvoviridae. AfaDV shares 78% nucleotide pairwise identity to the sea star associated densovirus (SSaDV), previously described as the putative causative agent of Sea Star Wasting Syndrome among sea stars from the Northwest Pacific. SSaDV was not found in specimens collected in this study, and the discovery of AfaDV might explain previous reports of SSaDV among sea stars from the Atlantic Coast. A qPCR assay was designed to assess tissue tropism, host specificity, and prevalence of AfaDV among wild populations of sea stars at five locations on the North American Atlantic Coast. AfaDV was detected in all three common sea star species (Asterias forbesi, Asterias rubens, and Henricia sp.) found in the region and was highly prevalent (80-100% of individuals tested, n=134), among populations collected at disparate sites 7 years apart. AfaDV was detected in the body wall, gonads, and pyloric caeca (digestive gland) of specimens but was not detected in their coelomic fluid. A significant difference in viral load was found between tissue types with the pyloric caeca having the highest viral load suggesting it is the primary site of viral replication in the animal. Further investigation of Asterias forbesi gonad tissue found germline cells (oocytes) to be virus positive suggesting a potential route of vertical transmission. Taken together, these observations show that the presence AfaDV is not an indicator of Sea Star Wasting Syndrome because AfaDV is a common constituent of these animals microbiome, regardless of health. These results broaden the understanding of echinoderm densoviruses outside the context of disease that suggest these viruses might form commensal or mutualistic relationships with their hosts.

microbiology↗

bioRxiv2018

Not-so-working memory: Drift in fMRI pattern representations during maintenance predicts errors in a visual working memory task

Working memory (WM) is critical to many aspects of cognition, but it frequently fails. Much WM research has focused on capacity limits, but even for single, simple features, the fidelity of individual representations is limited. Why is this? We used fMRI and a pattern-based index of \"representational drift\" to investigate how ongoing changes in brain activity patterns throughout the WM maintenance period predicted performance, using a delayed-match-to-sample task for a single item with a single critical feature: orientation. In trials where the target and probe stimuli matched, participants incorrectly reported more non-matches when their activity patterns drifted away from the target. In trials where the target and probe did not match, participants incorrectly reported more matches when their activity patterns drifted towards the probe. Our results suggest that WM errors are not simply due to unstructured noise, but also drift within representation space that can be indexed by neuroimaging.

neuroscience↗

bioRxiv2017

A Systems-Level Framework For Drug Discovery Identifies Csf1R As A Novel Anti-Epileptic Drug Target

The identification of mechanistically novel drug targets is highly challenging, particularly for diseases of the central nervous system. To address this problem we developed and experimentally validated a new computational approach to drug target identification that combines gene-regulatory information with a causal reasoning framework (\"causal reasoning analytical framework for target discovery\" - CRAFT). Starting from gene expression data, CRAFT provides a predictive functional genomics framework for identifying membrane receptors with a direction-specified influence over network expression. As proof-of-concept we applied CRAFT to epilepsy, and predicted the tyrosine kinase receptor Csf1R as a novel therapeutic target for epilepsy. The predicted therapeutic effect of Csf1R blockade was validated in two pre-clinical models of epilepsy using a small molecule inhibitor of Csf1R. These results suggest Csf1R blockade as a novel therapeutic strategy in epilepsy, and highlight CRAFT as a systems-level framework for predicting mechanistically new drugs and targets. CRAFT is applicable to disease settings other than epilepsy.

systems biology↗